TB is a deadly contagious disease caused by the infectious agent, Mycobacteriu tuberculosis. It kills 2 million people each year. The World Health Organization (WHO) 2001 annual report estimated that there would be 8.4 million new TB cases in 1999, up from 8.0 million in 1997. If the present trend continues, it is estimated that between 2000 and 2020, nearly one billion people will be newly infected, 200 million people will become ill and 35 million will die from TB. The spread of HIV/AIDS and the emergence of multidrug-resistant TB contribute to the worsening impact of this disease. Bacille Calmette-Guerin (BCG), an attenuated strain of Mycobacterium bovis, is currently the only available vaccine for the prevention of TB. In animal models of infection, BCG vaccination has been demonstrated to induce protective immunity against a M tuberculosis challenge (Baldwin et al., 1998). In humans, BCG vaccination has demonstrated consistent protection against the childhood forms of TB, especially meningitis. However, BCG vaccination is controversial due to variations in its efficacy for protecting adults from pulmonary TB (Fine, 1989; Colditz et al. , 1994; Sterne et al., 1998). Trials conducted in the 1940s and 1950s in developed countries such as the United Kingdom, Denmark and North America demonstrated the vaccine to be highly efficient (70-80%). However, in the single largest clinical trial, which took place in India in 1970s and involved more than 265,000 persons, BCG vaccination provided no detectable protection against pulmonary TB. Thus, there is an urgent need to generate an improved vaccine(s) to replace the BCG and to prevent TB.
Several explanations have been suggested for the variation in protective efficacy of BCG (Andersen, 2001). The most prominent hypothesis is that exposure to environmental mycobacteria sensitizes the host against mycobacteria in general, thereby providing heterologus immunity that obscures the potential benefits of BCG vaccination (Fine, 1995; Fine and Vynnycky, 1998). Furthermore, a recent study showed that the multiplication of BCG was inhibited in animals sensitized with environmental mycobacteria, and consequently BCG vaccination elicited only a transient immune response and failed to provide protective immunity against TB (Brandt et al., 2002). This study also supports the long-standing observation that the induction of immunity to TB requires productive infection by BCG. BCG is a live vaccine; killed BCG does not provide protection. Like M. tuberculosis, BCG is capable of forming granulomas and abscesses in various tissues in the infected host (Hogan et al., 2001). The ability of M. tuberculosis and M. bovis BCG to survive and persist within granulomas, a hostile environment with restricted access to nutrients and reduced oxygen tension, appears to be dependent on the ability of the bacteria to adapt their metabolism to the available source of carbohydrate, nitrogen, and energy (Barclay and Wheeler, 1989). A recent study revealed that fatty acids serve as a source of carbohydrates and are required for persistence of M. tuberculosis in mice and activated macrophages (McKinney et al., 2000). Following vaccination in immunocompetent individuals, BCG may persist for certain periods before it is eliminated from the host (Dunn and North 1995; Lagranderie et al., 1996; Moisan et al., 2001).
The key to developing a new and effective TB vaccine is to provide long-term protection (Orme, 2001; Young, 2000). Existing BCG vaccines impart protection against the manifestations of TB in children, but their efficacy wanes over a period of 10 to 15 years, presumably because the protective immunity induced by BCG is gradually lost (Orme, 2001). New strategies to developing an improved vaccine have included the use of attenuated mycobacteria, subunit vaccines and DNA vaccines (Andersen, 2001). However, none of these have proved to be more potent than, or even as effective as BCG. Survival and growth of M. bovis BCG is necessary for eliciting protective immunity. It has been shown that early treatment of infected mice with isoniazid to inhibit bacillary growth prevents the development of acquired resistance. BCG strains that persist for extended periods within the host are required in order to obtain more effective vaccines. As such, there is a need for novel, recombinant strains of Bacille Calmette-Guérin.